N-aralkylcarbonyl-piperazine and -homopiperazine compounds and personal care compositions comprising the same

ABSTRACT

A personal care composition comprising N-aralkylcarbonyl-piperazine and/or -homopiperazines. When such compounds are used in personal care compositions, they have been unexpectedly to enhance cell proliferation and epidermal thickness, traits associated with younger, healthy looking skin.

FIELD OF THE INVENTION

The present invention relates to novel N-aralkylcarbonyl-piperazine and-homopiperazine compounds and personal care compositions comprising oneor more of said compounds.

BACKGROUND OF THE INVENTION

Young and healthy looking skin is a desirable attribute worldwide andthe market for cosmetic products capable of improving our skinappearance is significant and growing.

As we age, our natural ability to maintain young and healthy lookingskin diminishes and, consequently, our skin appearance changes inresponse to the biological processes that take place within the skin atthe cellular level. Modulation of these processes at the skin surfacevia intervention of specific pathways with diverse cosmetic ingredientscan improve skin health and appearance. Numerous examples of howcosmetic ingredients can modulate appearance via this type ofintervention are well documented.

Increased cell proliferation and migration, as well as epidermalthickness are some of the traits associated with a younger and healthylooking skin phenotype. Among the various pathways leading to suchtraits, inhibition of the muscarinic cholinergic system, particularlythe muscarinic 3 receptor, has been shown to increase cell proliferationand migration in healthy skin. See for example, Grando et al,“Keratinocyte muscarinic acetylcholine receptors: immunolocalization andpartial characterization” Journal of Investigative Dermatology (1995),104, 95-100; Ndoye et al. “Identification and mapping of keratinocytemuscarinic acetylcholine receptor subtypes in human epidermis” Journalof investigative Dermatology (1998) 111, 410-416; Nguyen et al“Synergistic control of keratinocyte adhesion through muscarinic andnicotinic acetylcholine receptor subtypes” Exp. Cell. Res. (2004) 294,534-549; Kurzen et al. “The non-neuronal cholinergic system of humanskin” Horm. Metab. Res. (2007) 39, 125-137.

Muscarinic receptor antagonists have been claimed in medications used totreat skin diseases. For example, WO0110427 describes the use ofanti-muscarinic agents to treat skin disorders including psoriasis,atopic dermatitis, eczema, urticaria, acne, etc. WO09068876 describesthe use of muscarinic receptor antagonists with antibacterial and sebumsuppressive activities in the manufacture of medicaments to treatbacterial skin infections. Further, WO09150408 and WO09068876 describethe use of muscarinic receptor antagonists in compositions to treat acneand seborrhea, for example.

Various compositions comprising some N-aralkylcarbonyl-piperazinederivatives or related structures have been described, for example inUS20070004750 (Dow AgroSciences, LLC); WO2006056752 (Aztrazeneca UKLimited); Zha et al., “Synthesis and structure-activity relationshipstudies for hydantoins and analogues as voltage-gated sodium channelligands”, Journal of Medicinal Chemistry (2004) 47, 6519-6528;WO03037271 (Millenium Pharmaceuticals); WO9718203 (Merck Sharp and DohmeLimited); Carceller et al. “(Pyridylcyanomethyl)piperazines as orallyactive PAF antagonists”, Journal of Medicinal Chemistry (1992) 35,4118-4134 and EP441226; Di Paco et al. “Derivatives of ethylphenylaceticacid. I”, Farmaco, Edizione Scientifica (1956) 11, 540-548; Hromatka etal. “The synthesis of new acylpiperazines”, Monatshefte fuer Chemie(1954) 85, 1208-1214; Ogino et al. “Muscarinic M3 receptor antagonistswith (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxyphenylacetamidestructures. Part 2”, Bioorganic and Medicinal Chemistry Letters (2003)13, 2167-2172; WO09079392 and US2009069335 (Theravance Inc.). Howeverthe specific derivatives used are different from the compounds of ourinvention. Differences in molecular architecture will likely result indifferent physicochemical and biological properties. Our compounds, forexample, contain up to a single tertiary amine functional group(although the tertiary amine may be replaced by a second amide at the R₃site), but contain no secondary amine functional groups. As our pH datademonstrates, in going from a solution containing a secondary aminecompound (2.5% weight/volume) to a solution containing a tertiary aminecompound (2.5% weight/volume), the pH decreases from 10.0 to 8.5 forN-aralkylcarbonyl-piperazines (1.5 pH unit decrease) and from 9.9 to 9.0for N-aralkylcarbonyl-homopiperazines (0.9 pH unit decrease). Thisclearly demonstrates that our compounds are less basic than similarcompounds (by “similar” is meant a compound exactly the same butwherein, for example, R₃ is an alkyl group, such as methyl instead ofhydrogen and that therefore defines a tertiary amine instead of asecondary amine; see Example 31 versus 30 or 34 versus 33) havingsecondary amines. That is, they are less basic relative to compoundswhich have the same structure, but differ in that they have a secondaryamine in place of a tertiary amine. In general, compounds of theinvention will provide a drop in basicity of at least 0.3 pH units,preferably 0.3-4.0 pH units relative to the noted compounds whenmeasured in solution as defined below. Moreover, none of these compoundsnoted above are recognized for use as cosmetics providing personal carebenefits.

The novel N-aralkylcarbonyl-piperazines and -homopiperazine compounds ofthe invention have several advantages for use in personal carecompositions compared to N-aralkylcarbonyl-piperazine derivatives andmuscarinic receptor antagonists described in the prior art. For example,compounds of the invention are not quaternized, which distinguishes themfrom some of the currently used muscarinic receptor antagonists, forexample, oxyphenonium bromide, glycopyrrolate, ipatropium, andtiotropium to name a few. By “not quaternized” is meant that they do nothave an additional bond attaching an alkyl group to the nitrogen atom ofthe tertiary amine which provides a permanent positive charge.Quaternized compounds are less desirable because they do not penetrateskin as effectively compared to when they are in an unquaternized form.The novel unquarternized N-aralkylcarbonyls of the invention are thusbetter suited for skin applications.

As noted, the novel N-aralkylcarbonyls of our invention arenon-quaternized and contain a maximum of one tertiary amine group. Thus,in compounds of our invention (defined by Formula I below), for example,R₃ may be alkyl (forming a compound with one amide and one tertiaryamine group because of the alkyl at R₃); or R₃ may be a carbonyl group(C═O), forming a compound having amide groups at both N atoms. Further,because of the presence of at least one amide group (even if R₃ is alkyland forms a tertiary amine), the compounds of our invention have lowerpKa and are less basic than other muscarinic receptor antagonists knownin the art. More specifically, they are less basic than other muscarinicreceptor antagonists reported which either contain at least one basicamine group (e.g., primary or secondary amine) and/or, if they havetertiary amines, do not comprise an amide bond (which provides aninductive effect lowering the electron density of other potentialsecondary and tertiary amines) and therefore do not obtain lowered pKaand basicity (measured by lower pH in solution). In short, compared toother muscarinic receptor antagonists containing cyclic structures withsecondary or tertiary amine (alkylpyrrollidine, alkylpiperidine, N-alkylpyrrolidine, N-alkylpiperidine, etc.), the novel compounds of ourinvention have lower pKa and are less basic, as measured by dissolvingequimolar amounts of inventive or comparative compounds in organicsolvent and diluting with sufficient water to provide a 1 to 5%solution, preferably 2 to 4% solution (weight/volume) of the compound inthe water-organic solvent homogeneous solution. Preferably, the drop inpH between comparative compound and inventive compound, when measured insolution, will be 0.3 to 4 pH units.

Specifically, for example, the pH of a 2.5% solution of the tertiaryN-aralkylcarboxamido-piperazine (Example 3, ID 3c) is 8.5 compared toits corresponding secondary amine structure (N-methyl to N-Hreplacement) which has a pH of 10.0; this represents a 1.5 pH unitdecrease from comparative secondary amine (sec) to inventive tertiaryamine (tert) compound; and the pH of a 2.5% solution of the tertiaryN-aralkylcarbonyl-homopiperazine (Example 5, ID 3e) is 9.0 compared toits corresponding secondary amine structure which has a pH of 9.9; thisrepresents a 0.9 pH unit decrease from sec to tert. This clearlydemonstrates that compounds of the invention are less basic than similarcompound with corresponding secondary amines.

Some examples of piperazine compounds which are disclosed and whichdiffer from those of the invention because of the presence of primary orsecondary amines include WO 2009/079392 (amidine), US 2009/069335(guanidine), compounds in Ogino et al., Bioorganic & Medicinal chemistryLetters (BMCL) 13 (2003), 2167-217 (diofluoro compounds with primaryand/or secondary amines). In US 2008/269190 is disclosed a compoundwhere the piperidine group is quaternized to form an ammonium group.These quaternized-piperidine ammonium compounds represent a differentclass of compounds with different particularities compared to theircorresponding secondary or tertiary (non-quaternized) counterparts.Further, the ammonium structures have a permanent positive change(quaternary). For skin applications such compounds penetrate less andare less desirable.

Generally compounds with high pKa (typically providing solutions ofhigher pH) are less desirable for skin compositions as they can be morecorrosive and irritating to the skin. They can form charged species,which are difficult to formulate, and thus deliver less effectively tothe skin. By contrast, novel compounds of our invention are milder tothe skin (less basic), penetrate better because they are less charged,and are easier to formulate in personal care compositions. Further, thenovel N-aralkylcarbonylcompounds of the invention do not contain esterfunctional groups, unlike many of the currently used muscarinic receptorantagonists such as oxybutynin, hyoscyamine, dicyclomine, andpropiverine to name a few. Compounds with ester groups are lessdesirable for skin compositions since they are prone to hydrolysis onceformulated, especially under high heat storage conditions. Our compoundscontain tertiary amide bonds which are known to be more stable thantheir corresponding esters.

SUMMARY OF THE INVENTION

The present invention is based at least in part on the finding thatcertain novel N-aralkylcarbonyl-piperazines and -homopiperazines(Structure I below) are effective at inhibiting the muscarinic 3receptor and increasing cell proliferation, thereby providing cosmeticbenefits for personal care. The novel compounds of the invention have atleast one amide group defined by Structure I to the right (preferablydirectly to the right) of the R₁ and R₂ groups. The N—R₃, group may alsobe amide or a tertiary amine (no secondary or primary amine is present).Presence of only amide groups, or combination of amide and tertiaryamine groups provides molecules which have lower pKa and are less basic(as measured by drop in pH units, when pH of solution of comparativecompound is measured relative to pH of solution of inventive compound)than other muscarinic receptor antagonists of which applicants areaware.

The invention further relates to personal care compositions, preferablyanti-aging compositions, comprising the novelN-aralkylcarbonyl-piperazines and -homopiperazines compounds ofStructure I. The compositions of the invention may comprise one or moreN-aralkylcarbonylpiperazines; or one or more -homopiperazines; ormixtures of one or more compounds from each group. The invention alsoprovides methods of enhancing cell proliferation, enhancing cellmigration, and increasing epidermal thickness, all traits associatedwith younger, healthy skin and improving personal care. The methodcomprises applying to a person desirous of, or in need of, such enhancedcell attributes a composition comprising the novel compounds of theinvention. The composition may be applied in the form of a liquid,lotion, fluid cream, cream, gel, serum, paste, foam, spray, aerosol,roll-on, stick, solid, soft solid and/or any other cosmeticallyacceptable carrier for skin.

DETAILED DESCRIPTION OF THE INVENTION

Except in the examples, or where otherwise explicitly indicated, allnumbers in this description indicating amounts of material or conditionsof reaction, physical properties of materials and/or use are to beunderstood as modified by the word “about.” All amounts are by weight ofthe final composition, unless otherwise specified.

It should be noted that in specifying any range of concentration oramount, any particular upper concentration can be associated with anyparticular lower concentration or amount.

For the avoidance of doubt, the word “comprising” is intended to mean“including” but not necessarily “consisting of” or “composed of.” Inother words, the listed steps or options need not be exhaustive.

Unless indicated otherwise, all percentages for amount or amounts ofingredients used are to be understood to be percentages by weight.

The disclosure of the invention as found herein is to be considered tocover all embodiments as found in the claims as being multiply dependentupon each other irrespective of the fact that claims may be foundwithout multiple dependency or redundancy.

N-Aralkylcarbonyl-Piperazines and -Homopiperazines

Novel N-aralkylcarbonyl-piperazines and -homopiperazines compounds ofthe invention have Structure I as set forth below:

wherein n=0 or 1 andwherein when n=1, R₁ is selected from hydrogen or hydroxyl, R₂ isselected from cyclohexyl or cyclopentyl and R₃ is selected from thegroup consisting of C₁-C₃ alkyl (e.g., methylethyl) or C₁-C₄ arylalkyl(by which is meant a C₁ to C₄ alkyl group directly attached to the arylgroup, e.g., phenylbutyl); and when n=0, R₁ and R₂ are as defined above(e.g., R₁ is hydrogen or hydroxyl; R₂ is cyclohexyl or cyclopentyl) andR₃ is selected from the group consisting of C₁-C₈ alkyl, wherein the C₁to C₈ group may be linear, cyclic or branched; arylalkyl where the alkylcomponent has C₁ to C₄ chain, wherein the alkyl group may be linear,branched, saturated, or unsaturated, and wherein the alkyl group may beunsubstituted or substituted with one or two lower (C₁ to C₃) alkyl oralkoxy groups such as alcohol or ether; aroylalkyl, wherein the alkylgroup may be unsubstituted or substituted with one or two lower (C₁ toC₃) alkyl or alkoxy groups; arylalkanoyl; or aryloxyalkyl; and when n=0,R₁=hydrogen, R₂=cyclohexyl, R₃ cannot be benzyl or(E)-3-phenylprop-2-en-1-yl.

It will be understood that amine salts (e.g., halogen salts, tosylates,mesylates, carboxylates (e.g., C₂ to C₁₂ alkylcarboxylates which may belinear, branched or cyclic; and saturated or unsaturated), hydroxides,and any other counterions used in, for example, cosmetic industry) ofthe compound of Structure I are also considered to be covered by thestructure). Salt formation helps provide isolation and purificationbenefits prior to formulation. During formulation, the salt form can bechanged and optimized for maximum delivery.

In one preferred combination of the compound noted above, n=1, R₁ ishydroxyl, R₂ is cyclopentyl and R₃ is C₁ to C₃ alkyl, especially CH₃(see Example 5). In another preferred combination, n=0, R₁ is hydroxyl,R₂ is cyclopentyl and R₃ is arylalkyl, especially an aryl-C₃-alkyl groupsuch as phenylpropyl (see Example 11).

Other preferred combinations include the following:

-   -   n=1, R₁ is hydroxyl, R₂ is cyclohexyl and R₃ is methyl (see        Example 7);    -   n=1, R₁ is hydrogen, R₂ is cyclopentyl and R₃ is methyl (see        Example 6);    -   n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aryl-Ca-alkyl (branched) group, e.g., 4-phenylbut-2-yl (see        Example 14 where butyl group is branched);    -   n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aryl-C₄-alkyl (linear) group, e.g., 4-phenylbut-1-yl (see        Example 19 where butyl group is linear);    -   n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aryloxy-C₂-alkyl group, e.g., 2-phenoxyeth-1-yl (see Example        20);    -   n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aroyl-C₂-alkyl group, e.g., 3-phenyl-3-ketopropan-1-yl (see        Example 23);    -   n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aroyl-C₁-alkyl group, e.g., 2-phenyl-2-ketoeth-1-yl (see        Example 25) and    -   n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aryl-C₃-alkanoyl group, e.g., 3-phenylpropano-1-yl.

Other preferred compounds include the following:

-   -   1) n=1, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is methyl    -   2) n=1, R₁ is hydrogen, R₂ is cyclopentyl and R₃ is methyl    -   3) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        3-phenylprop-1-yl.    -   4) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        4-phenylbut-1-yl.    -   5) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        4-phenylbut-2-yl.    -   6) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aryloxy-C₂-alkyl group    -   7) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        2-phenoxyeth-1-yl.    -   8) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        2-phenoxyeth-1-yl.    -   9) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aroyl-C₁-alkyl group.    -   10) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is an        aroyl-C₂-alkyl group.    -   11) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        2-phenyl-2-ketoeth-1-yl.    -   12) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        2-phenyl-2-ketoeth-1-yl.    -   13) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        2-phenyl-2-ketoeth-1-yl.    -   14) n=0, R₁ is hydroxyl, R₂ is cyclopentyl and R₃ is        3-phenylpropano-1-yl.

Of course, combinations of any of the noted compounds are alsopreferred. As with primary and secondary amines, and as noted above,quaternary ammonium compounds, i.e. containing a permanently chargednitrogen, are not included within the scope of the invention. Quaternaryammonium compounds are not desirable because it is difficult to achieveeffective skin penetration for such quaternary ammonium compounds.

It can be observed from Structure I that one nitrogen atom on thepiperazine ring forms an amide (upper left nitrogen in Structure I) andone nitrogen generally forms a tertiary amine (although, as in Example27, it may also form an amide). As such, the compounds will typicallyhave lower pKa (and pH) than corresponding structures having secondaryor primary amine (see Comparative Example 31 versus Example 30).Preferably, pKa values are less than 9.0, preferably between 9 and 7.Lower pH or basicity is defined by having a drop in 0.3 to 4 pH unitswhen measured by dissolving equimolar amounts of inventive compounds orcomparative compounds (same as inventive but, unlike inventive which hasonly tertiary amine or amide, has secondary or primary amine) in organicsolvent, and diluting with sufficient water to provide 1 to 5% solution(weight/volume) of the compounds in the water-organic solventhomogeneous solution.

Further, compounds of the invention are not quaternized, and there ismore effective delivery to skin.

It is noted that the bond distance between the carbon to which R₁ and R₂are attached and the ring nitrogen attached to the carbonyl group isless than 3 angstroms. Typically, it is about 2.2 to 2.9, preferably 2.2to 2.7 angstroms, most preferably 2.4 to 2.6.

Amounts of the N-aralkylcarbonyl-piperazines and/or -homopiperazines incompositions of the invention may range from 0.001% to 20%, preferablyfrom 0.01 to 10%, more preferably from 0.1 to about 10%, optimally from0.1 to about 5% by weight of the composition. The compositions compriseone or more N-aralkylcarbonyl-piperazines; or one or moreN-aralkylcarbonyl-homopiperazines; or a mixture of one or more compoundsfrom each group.

Reagents & Analytical Methods

All reagents and solvents were obtained from commercial sources(Sigma-Aldrich, EMD Chemicals) and used without further purificationunless otherwise indicated. Parallel reactions and parallel solventremoval were performed using a Buchi Syncore reactor (Buchi Corporation,New Castle, Del.). Reaction monitoring was performed using thin layerchromatography (TLC). TLC was performed using silica gel 60 F254 plates(EMD Chemicals) and visualizing by UV (254 nm), 4% phosphomolybdic acid(PMA) in ethanol (EtOH), 4% ninhydrin in EtOH and/or using an iodinechamber. Flash chromatography (FC) was performed using a Biotage SP4system (Biotage LLC, Charlottesville, Va.). High performance liquidchromatography (HPLC) was performed using a Waters 2695 SeparationsModule equipped with a Waters 2996 Photodiode Array Detector andoperated with Empower Pro software (Waters Corp.). Separations werecarried out at 1 ml min on a Restek Pinnacle DB C18 column (5 um,4.6×150 mm) maintained at 30° C. Samples for HPLC were prepared bydissolving sample in mobile phase A:B (1:1) (1 mg/ml) and injecting 5-10μL onto the column. The mobile phase consisted of A=0.1% trifluoroaceticacid (TFA) in water and B=0.1% TFA in acetonitrile (ACN) operated usinggradient elution from 95:5 A:B to 5:95 A:B (gradient, 25 min) followedby 100% B (isocratic, 5 min). Gas Chromatography (GC) was performedusing an Agilent 7890A Gas Chromatograph equipped with an Agilent DB-5HT(15 m×0.32 mm; 0.1u) column and an FID detector heated @ 325° C. Sampleswere prepared at 25 ppm concentrations in acetone and the injectionvolume was 1 uL.

The air, helium and hydrogen flows were maintained @ 400, 25 and 30ml/min and the separation gradient consisted of 100° C. (isothermal, 1min), 15° C./min up to 250° C., 250° C. (isothermal, 4 min), 25° C./minup to 300° C., and 300° C. (isothermal, 3 min). Liquidchromatography/mass spectrometry (LC-MS) was performed using a FinniganMat LCQ Mass Spectrometer via direct infusion of samples (50 ppm) inmethanol and the total ion count monitored using electrospray ionizationin the (+) mode (ESI+). Proton (¹H) and Carbon (¹³C) nuclear magneticresonance (NMR) spectroscopy was performed using a Eft-60 NMRSpectrometer (Anasazi instruments, Inc.) and processed using WinNutssoftware (Acorn NMR, Inc.). Melting points were determined using aMeltemp apparatus (Laboratory Devices). Purity was determined byHPLC-UV/Vis and/or GC. All compounds were unequivocally confirmed byLC-MS and/or 1H NMR.

Purification Purity LC-MS Structure ID R₁ R₂ n R₃ Solvents ^(a) (%) ^(b)(M + H) ^(c) 3a cyclohexyl H 0 methyl 4% M in C 99.5 301.4 3bcyclopentyl H 0 methyl 4% M in C 99.5 287.4 3c cyclopentyl OH 0 methyl4% M in C 99.5 303.4 3d cyclopentyl H 0 hexyl 50% E in H 98.2 357.5 3ecyclopentyl OH 1 methyl 7% M in C 99.3 317.4 3f cyclopentyl H 1 methyl5% M in C 99.5 301.4 3g cyclohexyl OH 1 methyl 5% M in C 99.5 331.5 ^(a)All compounds purified by FC on silica gel. M = methanol; C =chloroform; E = ethyl acetate; H = hexanes. ^(b) Purity determined byHPLC-UV. ^(c) Expressed as [M + H]⁺ mass observed @ 100% abundance.

General Procedure I: Amines (1.0 equivalents) were added to solutions ofcarboxylic acid (1.0 equivalents), hydroxybenzotriazole (HOBt) (1.25equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDCl)(1.05 equivalents) in dimethylformamide (DMF) (0.7M solution), followedby diispropylethylamine (DIPEA) (1.0 equivalents) and the mixturestirred at RT for 16 h. The reactions were monitored by TLC using eithermethanol:chloroform (MeOH:CHCl₃) or ethyl acetate:hexanes (EA:HEX)mixtures and PMA staining until substantial amount of product wasobserved. The solutions were partitioned between 15% isopropyl alcohol(IPA) in CHCl₃:1N NaOH (5 vol:5 vol) and the organic layer dried withsodium sulfate (Na₂SO₄), filtered and the solvents removed in vacuo. Thecrude products were purified by FC on silica gel using suitable solventmixtures from MeOH:CHCl₃ or EA:HEX depending on TLC conditions. Forhighly polar compounds, TEA was added in the mobile phase atconcentrations anywhere from 0.1 to 1%. Product purity was determined byHPLC and product identity confirmed by LC-MS (ESI+) and/or ¹H NMR.

Purification Purity LC-MS Structure ID R₁ R₂ n R₃ X Solvents ^(a) (%)^(b) (M + H) ^(c) 7a cyclopentyl H 0 —CH₂Ph H 50% E in H 92.2 377.5 7bcyclopentyl H 0 —(CH₂)₂Ph H 30% E in H 99.0 391.6 7c cyclopentyl H 0trans-CH═CHPh H 45% E in H 89.6 389.6 7d cyclopentyl OH 0 —(CH₂)₂Ph H55% E in H 87.0 407.6 7e cyclopentyl OH 0 trans-CH═CHPh H 55% E in H92.8 405.6 7f cyclopentyl OH 0 —CH₂Ph H 55% E in H 77.4 393.5 7gcyclopentyl OH 0 —(CH₂)₂Ph methyl 55% E in H 95.6 421.6 7h cyclopentylOH 0 —CH₂(p-MeOPh) methyl 65% E in H 94.8 437.6 7i cyclopentyl OH 0-2-propylbenzo[d][1,3]dioxolane H 40% E in H 90.2 465.6 7j cyclopentylOH 1 —(CH₂)₂Ph H 1% M in C 92.6 421.6 ^(a) All compounds purified by FCon silica gel. M = methanol; C = chloroform; E = ethyl acetate; H =hexanes. ^(b) Purity determined by HPLC-UV. ^(c) Expressed as [M + H]⁺mass observed @ 100% abundance.

General Procedure II

STEP 1: t-Butyloxycarbonylpiperazine (1.0 equivalent) was added tosolutions of carboxylic acids (1.0 equivalents), HOBt (1.25 equivalents)and EDCl (1.05 equivalents) in DMF (0.7M solution), followed by DIPEA(1.0 equivalents) and the mixture stirred at RT for 16 h. The reactionswere monitored by TLC using either MeOH:CHCl₃ or EA:HEX mixtures and PMAstaining until substantial amount of product was observed. The reactionmixtures were diluted with MTBE (5 vol) and sequentially washed with0.1N HCl (1 vol), sat'd NaHCO₃ (1 vol), dried with Na₂SO₄, filtered andthe solvents removed in vacuo. The crude product H-S1-P was pure enoughto be used without purification for the next step.

STEP 2: Trifluoroacetic acid (5 ml per gram of 5) was added to asolution of 5 in CHCl₃ (5 ml per gram of 5) and allowed to sit at R.T.for 1 h. At this time, the solvents were removed in vacuo and theresidue dissolved in 15% IPA in CHCl₃ (15 ml per gram of 5), washed with1N NaOH:sat'd NaCl solution (1:1; 1 vol), dried with Na₂SO₄, filteredand the solvents removed in vacuo. The crude product 6 obtained wassufficiently pure to be used without purification for the next step.

STEP 3: Polystyrene cyanoborohydride resin (1.5 equivalents) was addedto mixtures of aldehydes (1.1 equivalents) or ketones (1.1 equivalents)and 6 (1 equivalent) in 1,2-dichloroethylene (DCE) (13 ml per gram of6), followed by glacial acetic acid (AcOH) (10 ml per gram of 6) and themixtures stirred in sealed vessels at R.T. for 1 to 16 h. The reactionswere monitored by TLC using either MeOH:CHCl₃ or EA:HEX mixtures and PMAstaining until substantial amount of product was observed. The solidswere filtered off and the filtrate diluted with 15% IPA in CHCl₃ (7vol), washed with 1N NaOH (1 vol), dried with Na₂SO₄, filtered and thesolvents removed in vacuo. The crude products were purified by FC onsilica gel using suitable solvent mixtures from MeOH:CHCl₃ or EA:HEXdepending on TLC conditions. For highly polar compounds, TEA was addedin the mobile phase at concentrations anywhere from 0.1 to 1%. Productpurity was determined by HPLC and product identity confirmed by LC-MS(ESI+) and/or ¹H NMR. Alternately, a more convenient work-up procedurefor STEP 3 involves filtering off the solids and washing with DCE (6 ml)and the filtrate stirred with AS-900 resin (10 g per gram of 6) for 1 h,dried by adding Na₂SO₄ and stirring, filtered and the solvents removedto give crude product which is purified further.

Purification Purity LC-MS Structure ID R₁ R₂ R₃ X Solvents ^(a) (%) ^(b)(M + H) ^(c) 9a cyclopentyl H —(CH₂)₂Cyclohexane Br 25% E in H 99.5383.6 9b cyclopentyl OH —(CH₂)₄Ph Br 55% E in H 92.6 421.6 9ccyclopentyl OH —(CH₂)₂OPh Br 60% E in H 98.0 409.5 9d cyclopentyl OH—(CH₂)₂-p-MeOPh Br 55% E in H 94.5 423.6 9e cyclopentyl OH—(CH₂)₂-(3,4-diMeO)Ph Br 100% E 97.0 453.6 9f cyclopentyl OH —(CH₂)₂COPhCl 100% E 99.0 421.6 9g cyclopentyl OH —CH₂CO-p-MeOPh Br 75% E in H 97.0437.6 9h cyclopentyl OH —CH₂COPh Br 50% E in H 99.0 407.5 ^(a) Allcompounds purified by FC on silica gel. M = methanol; C = chloroform; E= ethyl acetate; H = hexanes. ^(b) Purity determined by HPLC-UV. ^(c)Expressed as [M + H]⁺ mass observed @ 100% abundance.

General Procedure III: Amines 6 (1.0 equivalent) were added to solutionsof alkyl halides (1.0 equivalents) in DMF (10 ml per gram of 6),followed by TEA (1.1 equivalents) and the mixture microwaved @ 60° C.for 1 h or until complete consumption of starting materials. Thereactions were monitored by TLC using either MeOH:CHCl₃ or EA:HEXmixtures and PMA staining. Upon completion, the reaction mixtures werediluted with 15% IPA in CHCl₃ (10 vol), washed with 1N NaOH (1 vol),dried with Na₂SO₄, filtered and the solvents removed in vacuo. The crudeproducts were purified by FC on silica gel using suitable solventmixtures from MeOH:CHCl₃ or EA:HEX depending on TLC conditions. Forhighly polar compounds, TEA was added in the mobile phase atconcentrations anywhere from 0.1 to 1%. Product purity was determined byHPLC and product identity confirmed by LC-MS (ESI+) and/or ¹H NMR.Alternately, a more convenient work-up procedure was developed bydiluting reaction mixture with DMF (1 vol) and stirring with AS-900(OH—) resin (5 g of resin per gram of 6) for 1 h, filtered and thesolvents removed in vacuo to give crude product which is purifiedfurther.

Synthesis of Miscellaneous Compounds

Compound 11: Styrene oxide 10 (59.3 μL, 0.52 mmol) was added to asolution of 6b (150 mg, 0.52 mmol) in EtOH (2.4 ml) and microwaved @100° C. for 30 min. At this time, TLC (8% MeOH in CHCl₃) showed theformation of two major products and a small amount of SM. The solutionwas microwaved @ 100° C. for an additional 30 min, cooled to R.T. andstirred with AS-900 (OH—) (1 g) resin for 1 h, diluted with 15% IPA inCHCl₃ (6 ml) and sat'd NH₄Cl (6 ml), separated and the organic layerdried with Na₂SO₄, filtered and the solvents removed in vacuo to givecrude product as a colorless oil which solidified upon standing (190mg). The solid was suspended in E:H (1:1), filtered and washed withhexane. It was further crystallized from E:H to give pure MUS-837 (36mg). The filtrate was evaporated and purified by FC on silica gel using100% EA to give pure MUS-838 (20 mg). Product identity was confirmed by¹H NMR and LC-MS (M+H⁺ 409.5); purities (HPLC)˜95.6%.

Compound 13: 6b (200 mg, 0.7 mmol) was added to a solution of3-phenylpropionic acid 12 (104 mg, 0.7 mmol), HOBt (117 mg, 0.9 mmol)and EDCl (140 mg, 0.7 mmol) in DMF (1.5 ml), followed by TEA (97 μL, 0.7mmol) and the mixture stirred at R.T. for 16 h. At this time, TLC (60% Ein H) showed the clean formation of product and no S.M. The solution wasdiluted with EA (10 ml), washed sequentially with 10 mM HCl (10 ml),sat'd NaHCO₃ (10 ml), dried with Na₂SO₄, filtered and the solventsremoved to give a colorless gel (224 mg). The crude product was purifiedby FC on silica gel using 60% EA in hexanes to give pure product as acolorless gel (145 mg, 50%). Product identity was confirmed by ¹H NMRand LC-MS (M+H⁺ 421.5); purity (HPLC)˜99.5%.

Evaluation of N-Aralkylcarbonyl-Piperazines and -Homopiperazines

Muscarinic 3 Receptor Binding Assay

The muscarinic 3 receptor binding assay was adapted from Perkin Elmer.Briefly, assay buffer (60 μL of pH 7.4 phosphate saline buffer) wasadded to polypropylene round bottom 96-well microtiter plates, followedby CHO cell suspension expressing the human M3 receptor (1mgsuspension/ml; 20 ug membrane suspension per well). ³H-Scopolamine (20μL of a 7.5 nM solution) was added to each well and plates were shakenat room temperature for 2 h. Atropine (Sigma-Aldrich, St. Louis, Mo.)was used as a positive control. Test compounds and control samples wereprepared in DMSO (20 mM) and diluted to give a final concentration of 20μM. The reaction mixtures were then added to matrix 96-well GFCfiltration microtiter plates that had been previously pretreated with0.5% polyethylimine (100 μL) for 4 h and filtered. The binding reactionswere terminated by filtering through the GFC plates and washing &filtering with ice-cold phosphate saline buffer (5×100 μL). Once thefilters were dry, microscint scintillation cocktail (100 μL) was addedto each well, allowed to sit for 20 min and the plates analyzed using aTopCount scintillation counter. Test compounds which showed >50%reduction in ³H-scopolamine binding at a final concentration of 20 μMwere subjected to further serial dilutions and evaluated at variousconcentrations to determine their IC₅₀ value. Curve fitting of %inhibition versus concentration using Excell software alloweddetermination of IC₅₀ values for test compounds.

The IC₅₀ value is the concentration of compound needed to inhibit themuscarinic 3 receptor response by 50% of its maximum response. As theIC₅₀ value for a compound decreases below 10 μM, its antagonisticpotency against the muscarinic 3 receptor increases, which means less ofthe compound is needed to inhibit the receptor effectively. This thusleads, as noted, to enhanced cell proliferation, enhanced cellmigration, etc.

Use of 10 μM to show effect was based on the fact that applicants hadidentified internally a muscarinic 3 receptor antagonist with IC₅₀ of 10μM which demonstrated both increased epidermal thickness and increasedcell proliferation.

It should be noted that Ki-67 assay (discussed below) is aquantification assay associated with cell proliferation (higher thenumber of Ki67 positive cells when treated with compound, the higher thecell proliferation rate (associated with young healthy skin)), there isno necessary correlation between IC₅₀ value and cell proliferation. Thisis because muscarinic pathway (used for IC₅₀ test) is not the onlypathway associated with cell proliferation. So there is no guaranteethat inhibition of the pathway that leads to IC₅₀<10 μM necessarilyleads to cell proliferation. For example, a potent inhibitor of themuscarinic pathway (low IC₅₀) may hit other pathways which reduce cellproliferation. Further, there are various muscarinic receptor subtypeswhich may regulate in different ways. One compound may be a potentinhibitor of muscarinic 3 receptor (which should enhance cellproliferation), but also be a potent inhibitor of muscarinic 1, 2, 4 or5 receptor, and this might counter the response and lead to less or nocell proliferation.

Ki-67 Assay Using Human Living Skin Equivalents

The living skin equivalents (LSE) were processed as described byMargulis et al. “E-cadherin suppression accelerates squamous cellcarcinoma progression in three-dimensional, human tissue constructs”,Cancer Research (2005), 65, 1783-1791. The cultures were prepared usinga human neonatal fibroblast donor and a human aged primary keratinocytedonor from Cascade Biologics (Portland, Oreg.). Briefly, each dermalmatrix was prepared from fibroblasts (75K, P3) seeded in collagen andgrown for 1 wk in medium 106 (Cascade M106-500). The aged keratinocytes(P3) were added to the matrix at 275-300K cells per insert and grown for3 d submerged in JG-I media and exchanged for JG-II media on the thirdday, followed by air exposure 2 d later. At this point, the JG-II mediawas exchanged for JG-AL media until the end of the experiment. Four daysafter air exposure, samples were split into quadruplicate groups. LSEcultures were either left untreated, vehicle treated (0.1% DMSO) ordosed with test compounds delivered once per day for 4 d. At 8 d postair exposure, a 6 mm biopsy from each culture was taken and processedfor immunohistochemistry (IHC). Briefly, each biopsy was fixed for 3 hin neutral buffered formalin, transferred into ethanol (70%) andprocessed (tissue processing, embedding and sectioning) by AML labs(Baltimore, Md.). All precut sections were prepared for IHC using theSuperpicture IHC kit (Invitrogen, Carlsbad, Calif.). Primary rabbitpolyclonal Ki-67 antibody (Thermo Scientific, RB-9043-P, 1:1000) wasused as per manufacturer's instructions. Slides were counterstained withhaematoxylin and mounted with ClearMount water-soluble mounting medium(Invitrogen, Carlsbad, Calif.). Automated IHC processing for Ki-67(MACH4 AP) was performed on the Intellipath FLX (Biocare Medical).Slides were cleared in xylene and rehydrated in descending alcohols andbrought to water. High heat epitope retrieval was performed by immersingthe slides in a citrate buffer and then placing in a decloaking chamber(Biocare Medical). All subsequent steps were performed on theIntellipath FLX. Blocking, prode and polymer incubation was performedfor 10 minutes. Slides were incubated with Ki-67 (Thermo Fischer) for 1h at a 1:10,000 dilution. The chromagenic stain, Vuclan Fast Red(Biocare Medical) was added to the slides and incubated for 15 min. Theslides were then removed from the instrument, rinsed with water, driedin a 60° C. over for 1 h and placed in xylene and coverslipped. Thenumber of proliferation positive cells (Ki-67 positive) in the basallayer for all samples were determined by enlarging all images to thesame size, standardizing the sample area by drawing identicalrectangular boxes encompassing the basal layer showing Ki-67 antibodystaining and counting the cells using image photography with a 20×objective. The greater the number, the greater the proliferation. Alldata was analyzed for significance using the t-tests to generatep-values (p-values<0.01 represent 99% confidence, p values of 0.05represent 95% confidence both of which are statistically significant).Results were expressed as % increase of Ki-67 stained positive cellsover vehicle (0.1% DMSO).

pH Measurements

Solutions for pH measurements were prepared by dissolving specificamounts of test compounds into isopropyl alcohol (0.4 ml) and dilutingwith water (0.6 ml) to make 1 ml clear colorless homogeneous solutionsto give a final concentration of 79 mM for each test compound. Equimolaramounts of test compounds were used instead of weight % amounts toensure a fair (molar-basis) comparison between test compounds. Theconcentration of 79 mM was chosen based on compound 3e which representsa 2.5% solution (weight/volume). The pH of all test solutions wasmeasured @ 22° C. using a Corning pH meter model 430 with a flat surfacecombo w/RJ electrode. The pH meter was calibrated using standard pH 7 &12 buffers.

Compositions

Cosmetically Acceptable Carrier

Compositions of the invention also comprise a cosmetically acceptablevehicle dilutant, dispersant, or carrier for the active components inorder to facilitate their distribution when the composition is appliedto the skin.

Amounts of the carrier may range from about 1 to about 99.9%, preferablyfrom about 70 to about 95%, optimally from about 80 to about 90% byweight of the composition. Among the useful carriers are water,emollients, fatty acids, fatty alcohols, thickeners and combinationsthereof. The carrier may be aqueous, anhydrous or an emulsion.Preferably the compositions are aqueous, especially water and oilemulsions of the W/O or O/W type or multiple emulsions of the W/O/W orO/W/O variety. Water when present may be in amounts ranging from about 5to about 95%, preferably from about 20 to about 70%, optimally fromabout 35 to about 60% by weight.

Emollient materials may serve as cosmetically acceptable carriers. Thesemay be in the form of silicone oils, natural or synthetic esters,hydrocarbons, alcohols and fatty acids.

Amounts of the emollients may range anywhere from about 0.1 to about95%, preferably between about 1 and about 50% by weight of thecomposition.

Silicone oils may be divided into the volatile and non-volatile variety.The term “volatile” as used herein refers to those materials which havea measurable vapor pressure at ambient temperature. Volatile siliconeoils are preferably chosen from cyclic (cyclomethicone) or linearpolydimethylsiloxanes containing from 3 to 9, preferably from 5 to 6,silicon atoms.

Non-volatile silicone oils useful as an emollient material includepolyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxanecopolymers. The essentially non-volatile polyalkyl siloxanes usefulherein include, for example, polydimethyl siloxanes with viscosities offrom about 5×10⁻⁶ to 0.1 m²/s at 25° C. Among the preferred non-volatileemollients useful in the present compositions are the polydimethylsiloxanes having viscosities from about 1×10⁻⁵ to about 4×10⁻⁴ m²/s at25° C.

Another class of non-volatile silicones are emulsifying andnon-emulsifying silicone elastomers. Representative of this category isDimethicone/Vinyl Dimethicone Crosspolymer available as Dow Corning9040, General Electric SFE 839, and Shin-Etsu KSG-18. Silicone waxessuch as Silwax WS-L (Dimethicone Copolyol Laurate) may also be useful.

Among the ester emollients are:

-   a) Alkyl esters of saturated fatty acids having 10 to 24 carbon    atoms. Examples thereof include behenyl neopentanoate, isononyl    isonanonoate, isopropyl myristate and octyl stearate.-   b) Ether-esters such as fatty acid esters of ethoxylated saturated    fatty alcohols.-   c) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acid    esters, diethylene glycol mono- and di-fatty acid esters,    polyethylene glycol (200-6000) mono- and di-fatty acid esters,    propylene glycol mono- and di-fatty acid esters, polypropylene    glycol 2000 monostearate, ethoxylated propylene glycol monostearate,    glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty    esters, ethoxylated glyceryl mono-stearate, 1,3-butylene glycol    monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol    fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene    sorbitan fatty acid esters are satisfactory polyhydric alcohol    esters. Particularly useful are pentaerythritol, trimethylolpropane    and neopentyl glycol esters of C₁-C₃₀ alcohols.-   d) Wax esters such as beeswax, spermaceti wax and tribehenin wax.-   e) Sugar ester of fatty acids such as sucrose polybehenate and    sucrose polycottonseedate.

Natural ester emollients principally are based upon mono-, di- andtri-glycerides. Representative glycerides include sunflower seed oil,cottonseed oil, borage oil, borage seed oil, primrose oil, castor andhydrogenated castor oils, rice bran oil, soybean oil, olive oil,safflower oil, shea butter, jojoba oil and combinations thereof. Animalderived emollients are represented by lanolin oil and lanolinderivatives. Amounts of the natural esters may range from about 0.1 toabout 20% by weight of the compositions. Hydrocarbons which are suitablecosmetically acceptable carriers include petrolatum, mineral oil,C₁₁-C₁₃ isoparaffins, polybutenes and especially isohexadecane,available commercially as Permethyl 101A from Presperse Inc.

Fatty acids having from 10 to 30 carbon atoms may also be suitable ascosmetically acceptable carriers. Illustrative of this category arepelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic,linoleic, linolenic, hydroxystearic and behenic acids and mixturesthereof.

Fatty alcohols having from 10 to 30 carbon atoms are another usefulcategory of cosmetically acceptable carrier. Illustrative of thiscategory are stearyl alcohol, lauryl alcohol, myristyl alcohol, oleylalcohol and cetyl alcohol and mixtures thereof.

Thickeners can be utilized as part of the cosmetically acceptablecarrier of compositions according to the present invention. Typicalthickeners include crosslinked acrylates (e.g. Carbopol 982®),hydrophobically-modified acrylates (e.g. Carbopol 1382®),polyacrylamides (e.g. Sepigel 305®), acryloylmethylpropane sulfonicacid/salt polymers and copolymers (e.g. Aristoflex HMB® and AVC®),cellulosic derivatives and natural gums. Among useful cellulosicderivatives are sodium carboxymethylcellulose, hydroxypropylmethocellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose and hydroxymethyl cellulose. Natural gums suitable for thepresent invention include guar, xanthan, sclerotium, carrageenan, pectinand combinations of these gums. Inorganics may also be utilized asthickeners, particularly clays such as bentonites and hectorites, fumedsilicas, talc, calcium carbonate and silicates such as magnesiumaluminum silicate (Veegum®). Amounts of the thickener may range from0.0001 to 10%, usually from 0.001 to 1%, optimally from 0.01 to 0.5% byweight of the composition.

Preferred are emollients that can be used, especially for productsintended to be applied to the face, to improve sensory properties andare chosen from the group of oils that do not form stiff gels withcompounds of the invention; these include polypropylene glycol-14 butylether otherwise known as Tegosoft PBE, or PPG15 stearyl ether such asTegosoft E, other oils such as esters, specifically, isopropylmyristate, isopropyl palmitate, other oils could include castor oils andderivatives thereof.

Humectants of the polyhydric alcohol-type can be employed ascosmetically acceptable carriers. Typical polyhydric alcohols includeglycerol, polyalkylene glycols and more preferably alkylene polyols andtheir derivatives, including propylene glycol, dipropylene glycol,polypropylene glycol, polyethylene glycol and derivatives thereof,sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol,isoprene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylatedglycerol and mixtures thereof. The amount of humectant may rangeanywhere from 0.5 to 50%, preferably between 1 and 15% by weight of thecomposition.

Skin moisturizers, e.g. hyaluronic acid and/or its precursor N-acetylglucosamine may be included. N-acetyl glucosamine may be found in sharkcartilage or shitake mushrooms and are available commercially fromMaypro Industries, Inc (New York). Other preferred moisturizing agentsinclude hydroxypropyl tri(C₁-C₃ alkyl)ammonium salts. These salts may beobtained in a variety of synthetic procedures, most particularly byhydrolysis of chlorohydroxypropyl tri(C₁-C₃ alkyl)ammonium salts. A mostpreferred species is 1,2-dihydroxypropyltrimonium chloride, wherein theC₁-C₃ alkyl is a methyl group. Amounts of the salt may range from about0.2 to about 30%, and preferably from about 0.5 to about 20%, optimallyfrom about 1% to about 12% by weight of the topical composition,including all ranges subsumed therein.

Ordinarily the C₁-C₃ alkyl constituent on the quaternized ammonium groupwill be methyl, ethyl, n-propyl, isopropyl or hydroxyethyl and mixturesthereof. Particularly preferred is a trimethyl ammonium group knownthrough INCl nomenclature as a “trimonium” group. Any anion can be usedin the quat salt. The anion may be organic or inorganic with provisothat the material is cosmetically acceptable. Typical inorganic anionsare halides, sulfates, phosphates, nitrates and borates. Most preferredare the halides, especially chloride. Organic anionic counter ionsinclude methosulfate, toluoyl sulfate, acetate, citrate, tartrate,lactate, gluconate, and benzenesulfonate.

Still other preferred moisturizing agents which may be used, especiallyin conjunction with the aforementioned ammonium salts includesubstituted urea like hydroxymethyl urea, hydroxyethyl urea,hydroxypropyl urea; bis(hydroxymethyl) urea; bis(hydroxyethyl) urea;bis(hydroxypropyl) urea; N,N′-dihydroxymethyl urea; N,N′-di-hydroxyethylurea; N,N′-di-hydroxypropyl urea; N,N,N′-tri-hydroxyethyl urea;tetra(hydroxymethyl) urea; tetra(hydroxyethyl) urea; tetra(hydroxypropylurea; N-methyl, N′-hydroxyethyl urea; N-ethyl-N′-hydroxyethyl urea;N-hydroxypropyl-N′-hydroxyethyl urea and N,N′dimethyl-N-hydroxyethylurea. Where the term hydroypropyl appears, the meaning is generic foreither 3-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-i-propyl or2-hydroxy-i-propyl radicals. Most preferred is hydroxyethyl urea. Thelatter is available as a 50% aqueous liquid from the National Starch &Chemical Division of ICI under the trademark Hydrovance.

Amounts of substituted urea that may be used in the topical compositionof this invention range from about 0.01 to about 20%, and preferably,from about 0.5 to about 15%, and most preferably, from about 2 to about10% based on total weight of the composition and including all rangessubsumed therein.

When ammonium salt and/or substituted urea are used, in a mostespecially preferred embodiment at least from about 0.01 to about 25%,and preferably, from about 0.2 to about 20%, and most preferably, fromabout 1 to about 15% humectant, like glycerine, is used, based on totalweight of the topical composition and including all ranges subsumedtherein.

Form of the Composition

The compositions of the present invention may be formulated as lotion,fluid cream, cream, gel, serum, spray, roll-on, stick. They may besolids or soft-solids as well. In preferred “non-solidness” form,compositions have viscosity, e.g. as measured using a BrookfieldDV-I+viscometer (20 RPM, RV6, 30 seconds), which in general is in therange of from 1 Pas to 500 Pas, preferably from 1 Pas to 200 Pas, morepreferably from 2 Pas to 100 Pas, most preferably from 3 Pas to 50 Pas(measured at room temperature).

Preferably, compositions of the invention are leave-on compositions.That is, they are intended to be applied to remain on the skin. Theseleave-on compositions are to be distinguished from compositions whichare applied to the skin and subsequently removed either by washing,rinsing, wiping, or the like either after or during the application ofthe product. Surfactants typically used for rinse-off compositions havephysico-chemical properties giving them the ability to generatefoam/lather in-use with ease of rinse; they can consist of mixtures ofanionic, cationic, amphoteric, and nonionic. Surfactants used inleave-on compositions on the other hand are not required to have suchproperties. Rather, as leave-on compositions, they are not intended tobe rinsed-off, they need to be non-irritating, and therefore it isdesirable to minimize the total level of surfactant and the total levelof anionic surfactant in skin leave-on compositions. Therefore, thecompositions of the present invention preferably contain, with respectto surfactants, predominantly nonionic surfactants. The anionicsurfactants are present in an amount of at most 5%, preferably from 0.01to 4%, more preferably from 0.01 to 3%, most preferably from 0.01 to 2%and optimally are substantially absent (less than 1%, preferably lessthan 0.1%, or even less than 0.01%). Salts ofN-aralkylcarbonyl-piperazines and -homopiperazines are not consideredanionic surfactants herein. Also, while salts of alkylcarboxlate may ormay not be considered as anionic surfactants, their use is typicallydesirable in leave-on compositions and so need not be minimized. Thetotal level of surfactant in the inventive compositions is preferably nomore than 10%, more preferably below 8%, most preferably at most 5%.

The compositions of the present invention are typically in the form ofemulsions, which may be oil-in-water, or water-in-oil; preferably thecompositions are oil-in-water emulsions. Another preferred format is acream, furthermore preferably one which has a vanishing cream base.Vanishing cream base is one which comprises 5 to 40% fatty acid and 0.1to 20% soap. In such creams, the fatty acid is preferably substantiallya mixture of stearic acid and palmitic acid and the soap is preferablythe potassium salt of the fatty acid mixture, although other counterionsand mixtures thereof can be used. The fatty acid in vanishing cream baseis often prepared using hystric acid which is substantially (generallyabout 90 to 95%) a mixture of stearic acid and palmitic acid. A typicalhystric acid comprises about 52-55% palmitic acid and 45-48% stearicacid of the total palmitic-stearic mixture. Thus, inclusion of hystricacid and its soap to prepare the vanishing cream base is within thescope of the present invention. It is particularly preferred that thecomposition comprises higher than 7%, preferably higher than 10%, morepreferably higher than 12% fatty acid.

Optional Ingredients

Compositions of the invention may be used to deliver a variety of skinconditioning benefits. “Conditioning” as used herein includes preventionand treatment of aged and photo-damaged skin, appearance of wrinkles,age spots, aged skin, increasing skin firmness, increasing stratumcorneum flexibility, lightening skin color, controlling sebum excretionand generally increasing the quality and radiance of skin. Thecomposition may be used to improve fibroblast metabolic activity andproliferation, skin desquamation and epidermal differentiation andimprove skin appearance or general aesthetics.

Preferably the pH of the inventive compositions is less than about 8,more preferably is in the range of from 3.5 to 8.0, most preferably isfrom 5 to 7.8 Once the compound penetrates the skin, it will partitionthrough the layers of the skin and may experience pH changes as well. Ifthe pKa of the compound is too high (meaning that it will be (+)-chargedfor the most part), the compound will not be sensitive to these pHchanges and may not travel and/or partition through the lipophilic(neutral) cell membranes of the skin effectively to reach its targetsite (epidermis/dermis). The lower the pKa of the compound and thecloser it is to neutral pH, the higher the probability that the compoundwill be able to partition effectively through the layers of the skin toits target site. N-aralkylcarbonyl-piperazine and -homopiperazinecompound(s) are preferably included in the inventive compositions in anamount of from 0.001 to 20%, more preferably from 0.01 to 10%, mostpreferably from 0.1 to 10%, and optimally from 0.1 to 5%. The amounts ofthe compound(s) or salts thereof are not meant to be included within thesurfactants amounts herein.

Surfactants

Total concentration of the surfactant when present may range from about0.1 to about 90%, preferably from about 1 to about 40%, optimally fromabout 1 to about 20% by weight of the composition, and being highlydependent upon the type of personal care product. The surfactant may beselected from the group consisting of anionic, nonionic, cationic andamphoteric actives. Particularly preferred nonionic surfactants arethose with a C₁₀-C₂₀ fatty alcohol or acid hydrophobe condensed withfrom 2 to 100 moles of ethylene oxide or propylene oxide per mole ofhydrophobe; C₂-C₁₀ alkyl phenols condensed with from 2 to 20 moles ofalkylene oxide; mono- and di-fatty acid esters of ethylene glycol; fattyacid monoglyceride; sorbitan, mono- and di-C₈-C₂₀ fatty acids; andpolyoxyethylene sorbitan as well as combinations thereof. Alkylpolyglycosides and saccharide fatty amides (e.g. methyl gluconamides)and trialkylamine oxides are also suitable nonionic surfactants.

Useful amphoteric surfactants include cocoamidopropyl betaine, C₁₂-C₂₀trialkyl betaines, sodium lauroamphoacetate, and sodiumlaurodiamphoacetate.

Preferred anionic surfactants include soap, alkyl ether sulfates andsulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates,alkyl and dialkyl sulfosuccinates, C₈-C₂₀ acyl isethionates, C₈-C₂₀alkyl ether phosphates, C₈-C₂₀ sarcosinates, C₈-C₂₀ acyl lactylates,sulfoacetates and combinations thereof. In compositions containingaralkylcarboxamio-piperazine and -homopiperazine compound(s), thepreferred surfactants are high HLB nonionic sugar surfactant with an HLBof at least 7 selected from the group consisting of alkylpolyglucosides, sugar fatty acid esters, aldobionamides, polyhydroxyfatty acid amides and mixtures thereof. Rheology Modifier

A rheology modifier may be included and is selected from the groupconsisting of silica such as fumed silica or hydrophilic silicas andclays such as magnesium aluminum silicate, betonites, hectorite,laponite, and mixtures thereof. A rheology modifier is employed in anamount of from 0.01 to 2%, preferably from 0.05 to 1%.

Skin Benefit Ingredients

The inventive composition preferably includes an additional skinlightening compound, to obtain optimum skin lightening performance at anoptimum cost. Illustrative substances are placental extract, lacticacid, niacinamide, arbutin, kojic acid, ferulic acid, hydroquinone,resorcinol and derivatives including 4-substituted resorcinols andcombinations thereof. More preferably such additional skin lighteningcompound is a tyrosinase inhibitor to complement the melanogenesisinhibition activity of the substituted monoamines, most preferably acompound selected from the group consisting of kojic acid, hydroquinoneand 4-substituted resorcinol. Also dicarboxylic acids represented by theformula HOOC-(CxHy)-COOH where x=4 to 20 and y=6 to 40 such as azelaicacid, sebacic acid, oxalic acid, succinic acid, fumaric acid,octadecenedioic acid or their salts or a mixture thereof, mostpreferably fumaric acid or salt thereof, especially di-sodium salt. Acombination of hydroxyl stearic acid (12-HSA) with fumaric acid or saltsthereof is preferred, especially for skin lightening formulations.Amounts of these agents may range from about 0.1 to about 10%,preferably from about 0.5 to about 2% by weight of the composition. Itis preferred that the skin lightening coactive according to theinvention is vitamin B3 or a derivative thereof and is selected from thegroup consisting of niacinamide, nicotinic acid esters, non-vasodilatingesters of nicotinic acid, nicotinyl amino acids, nicotinyl alcoholesters of carboxylic acids, nicotinic acid N-oxide, niacinamide N-oxideand mixtures thereof.

Sunscreen is another preferred ingredient of the inventive compositions.Particularly preferred are such materials as ethylhexylp-methoxycinnamate (available as Parsol MCX®), Avobenzene (available asParsol 1789®), octylsalicylate (available as Dermablock OS®),tetraphthalylidene dicamphor sulfonic acid (available as Mexoryl SX®),benzophenone-4 and benzophenone-3 (Oxybenzone). Inorganic sunscreenactives may be employed such as microfine titanium dioxide, zinc oxide,polyethylene and various other polymers. By the term “microfine” ismeant particles of average size ranging from about 10 to about 200 nm,preferably from about 20 to about 100 nm. Amounts of the sunscreenagents when present may generally range from 0.1 to 30%, preferably from2 to 20%, optimally from 4 to 10% by weight of the composition.

More preferred inventive compositions include both the additional skinlightening compound, especially tyrosinase inhibitor, and a sunscreencompound.

Another preferred ingredient of the inventive compositions is aretinoid. As used herein, “retinoid” includes all natural and/orsynthetic analogs of Vitamin A or retinol-like compounds which possessthe biological activity of Vitamin A in the skin as well as thegeometric isomers and stereoisomers of these compounds. The retinoid ispreferably retinol, retinol esters (e.g., C₂-C₂₂ alkyl esters ofretinol, including retinyl palmitate, retinyl acetate, retinylpropionate), retinal, and/or retinoic acid (including all-trans retinoicacid and/or 13-cis-retinoic acid), more preferably retinoids other thanretinoic acid. These compounds are well known in the art and arecommercially available from a number of sources, e.g., Sigma ChemicalCompany (St. Louis, Mo.), and Boerhinger Mannheim (Indianapolis, Ind.).Other retinoids which are useful herein are described in U.S. Pat. No.4,677,120 issued Jun. 30, 1987 to Parish et al.; U.S. Pat. No. 4,885,311issued Dec. 5, 1989 to Parish et al.; U.S. Pat. No. 5,049,584 issuedSep. 17 1991 to Purcell et al.; U.S. Pat. No. 5,124,356 issued Jun. 23,1992 to Purcell et al.; and US Pat. No. Reissue 34,075 issued Sep. 221992 to Purcell et al. Other suitable retinoids are tocopheryl-retinoate[tocopherol ester of retinoic acid (trans- or cis-), adapalene{6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid}, and tazarotene(ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate).Preferred retinoids are retinol, retinyl palmitate, retinyl acetate,retinyl propionate, retinal and combinations thereof. The retinoid ispreferably substantially pure, more preferably essentially pure. Thecompositions of this invention may contain a safe and effective amountof the retinoid, such that the resultant composition is safe andeffective for regulating keratinous tissue condition, preferably forregulating visible and/or tactile discontinuities in skin, morepreferably for regulating signs of skin aging, even more preferably forregulating visible and/or tactile discontinuities in skin textureassociated with skin aging. The compositions preferably contain from orabout 0.005% to or about 2%, more preferably 0.01% to or about 2%,retinoid. Retinol is preferably used in an amount of from or about 0.01%to or about 0.15%; retinol esters are preferably used in an amount offrom or about 0.01% to or about 2% (e.g., about 1%); retinoic acids arepreferably used in an amount of from or about 0.01% to or about 0.25%;tocopheryl-retinoate, adapalene, and tazarotene are preferably used inan amount of from or about 0.01% to or about 2%.

Preservatives can desirably be incorporated into the cosmeticcompositions of this invention to protect against the growth ofpotentially harmful microorganisms. Suitable traditional preservativesfor compositions of this invention are alkyl esters ofpara-hydroxybenzoic acid. Other preservatives which have more recentlycome into use include hydantoin derivatives, propionate salts, and avariety of quaternary ammonium compounds. Cosmetic chemists are familiarwith appropriate preservatives and routinely choose them to satisfy thepreservative challenge test and to provide product stability.Particularly preferred preservatives are phenoxyethanol, methyl paraben,propyl paraben, imidazolidinyl urea, sodium dehydroacetate and benzylalcohol. The preservatives should be selected having regard for the useof the composition and possible incompatibilities between thepreservatives and other ingredients in the emulsion. Preservatives arepreferably employed in amounts ranging from 0.01% to 2% by weight of thecomposition.

Compositions of the present invention may include vitamins. Illustrativevitamins are Vitamin A (retinol), Vitamin B₂, Vitamin B₃ (niacinamide),Vitamin B₆, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, Vitamin K andBiotin. Derivatives of the vitamins may also be employed. For instance,Vitamin C derivatives include ascorbyl tetraisopalmitate, magnesiumascorbyl phosphate and ascorbyl glycoside. Derivatives of Vitamin Einclude tocopheryl acetate, tocopheryl palmitate and tocopheryllinoleate. DL-panthenol and derivatives may also be employed. Aparticularly suitable Vitamin B₆ derivative is Pyridoxine Palmitate.Flavonoids may also be useful, particularly glucosyl hesperidin, rutin,and soy isoflavones (including genistein, daidzein, equol, and theirglucosyl derivatives) and mixtures thereof. Total amount of vitamins orflavonoids when present may range from 0.0001 to 10%, preferably from0.01% to 1%, optimally from 0.1 to 0.5% by weight of the composition.

Another type of useful substance can be that of an enzyme such asoxidases, proteases, lipases and combinations. Particularly preferred issuperoxide dismutase, commercially available as Biocell SOD from theBrooks Company, USA.

Desquamation promoters may be present. Illustrative are themonocarboxylic acids. Monocarboxylic acids may be substituted orunsubstituted with a carbon chain length of up to 16. Particularlypreferred carboxylic acids are the alpha-hydroxycarboxylic acids,beta-hydroxycarboxylic or polyhydroxycarboxylic acids. The term “acid”is meant to include not only the free acid but also salts and C₁-C₃₀alkyl or aryl esters thereof and lactones generated from removal ofwater to form cyclic or linear lactone structures. Representative acidsare glycolic, lactic malic and tartaric acids. A representative saltthat is particularly preferred is ammonium lactate. Salicylic acid isrepresentative of the beta-hydroxycarboxylic acids. Amounts of thesematerials when present may range from about 0.01 to about 15% by weightof the composition. Other phenolic acids include ferulic acid, salicylicacid, kojic acid and their salts.

A variety of herbal extracts may optionally be included in compositionsof this invention. Illustrative are pomegranate, white birch (BetulaAlba), green tea, chamomile, licorice and extract combinations thereof.The extracts may either be water soluble or water-insoluble carried in asolvent which respectively is hydrophilic or hydrophobic. Water andethanol are the preferred extract solvents.

Also included may be such materials as resveratrol, alpha-lipoic acid,ellagic acid, kinetin, retinoxytrimethylsilane (available from ClariantCorp. under the Silcare 1M-75™), dehydroepiandrosterone (DHEA) andcombinations thereof. Ceramides (including Ceramide 1, Ceramide 3,Ceramide 3B, Ceramide 6 and Ceramide 7) as well as pseudoceramides mayalso be utilized for many compositions of the present invention but mayalso be excluded. Amounts of these materials may range from about0.000001 to about 10%, preferably from about 0.0001 to about 1% byweight of the composition.

Colorants, opacifiers and abrasives may also be included in compositionsof the present invention. Each of these substances may range from about0.05 to about 5%, preferably between 0.1 and 3% by weight of thecomposition.

The compositions of the present invention may contain a safe andeffective amount of a peptide active selected from pentapeptides,derivatives of pentapeptides, and mixtures thereof. As used herein,“pentapeptides” refers to both the naturally occurring pentapeptides andsynthesized pentapeptides. Also useful herein are naturally occurringand commercially available compositions that contain pentapeptides. Apreferred commercially available pentapeptide derivative-containingcomposition is Matrixyl™, which is commercially available from Sederma,France. The pentapeptides and/or pentapeptide derivatives are preferablyincluded in amounts of from about 0.000001% to about 10%, morepreferably from about 0.000001% to about 0.1%, even more preferably fromabout 0.00001% to about 0.01%, by weight of the composition. Inembodiments wherein the pentapeptide-containing composition Matrixyl™ isused, the resulting composition preferably contains from about 0.01% toabout 50%, more preferably from about 0.05% to about 20%, and even morepreferably from about 0.1% to about 10%, by weight of the resultingcomposition of Matrixyl™.

Additional peptides, including but not limited to, di-, tri-, andtetrapeptides and derivatives thereof, and poly amino acid sequences ofmolecular weight from 200-20000. Amino acids may be naturally occurringor synthetic, dextro or levo, straight chain or cyclized and may beincluded in the compositions of the present invention in amounts thatare safe and effective. As used herein, “peptides” refers to both thenaturally occurring peptides and synthesized peptides. Also usefulherein are naturally occurring and commercially available compositionsthat contain peptides.

Suitable dipeptides for use herein include Carnosine. Preferredtripeptides and derivatives thereof may be purchased as Biopeptide CL™.and a copper derivative sold commercially as lamin, from Sigma (St.Louis, Mo.).

Further ingredients useful in skin care compositions herein may beselected from any and all: skin conditioning agents, skin feel mildnessagents, suspending agents, auxiliary thickening agents, viscositycontrol agents, dispersants, solubilizing/clarifying agents,stabilizers, opacifiers/pearlescent agents, chelating/sequesteringagents, hydrotropes, bactericides/fungicides, antioxidants, pH controlagents, buffering agents, colorants and perfumes/fragrances, water,other optional ingredients (auxiliary agents) and the like.

The compositions of the present invention can also be optionally,incorporated into a water insoluble substrate for application to theskin such as in the form of a treated wipe.

Method of Making Compositions

Compositions within the scope of this invention were prepared in thefollowing manner. Mix all water soluble ingredients includingpreservatives, thickening polymer, optionally glycerine, and water andheat to a temperature of 70-90° C. In a separate vessel mix all oilsoluble ingredients including sugar surfactant andN-aralkylcarbonyl-piperazine and/or N-aralkylcarbonyl-homopiperazines toa temperature of 70-90° C. Add the oil phase to the water phase at atemperature of 70-90° C. with agitation. Optionally add niacinamide at45° C. followed by addition of fragrance and phenoxyethanol at 40° C.Cool the mixture to room temperature with mixing.

Method of Using Compositions

Composition according to the invention is intended primarily as aproduct for topical application to human skin, especially as an agentfor conditioning and smoothening the skin, and preventing or reducingthe appearance of wrinkled or aged skin, or age spots, or lightening ofthe skin.

More specifically, using compounds of the invention, the compositionsare intended to enhance cell proliferation, enhance cell migrationand/or increase epidermal thickness, all traits associated with younger,healthier skin.

In use, a small quantity of the composition, for example from 1 to 5 ml,is applied to exposed area of the skin, from a suitable container orapplicator and, if necessary, it is then spread over and/or rubbed intothe skin using the hand or fingers or a suitable device.

The invention will now be further illustrated in the followingnon-limiting examples.

EXAMPLES

Representative N-aralkylcarbonyl-piperazines and -homopiperazines ofStructure I within the scope of the invention were investigated forinhibition of the muscarinic 3 receptor and the ability to induce cellproliferation in living skin equivalents.

The results show that compounds included in this invention effectivelyinhibit the muscarinic 3 receptor (Table 1). Specifically, compound withIC₅₀ value (defined as the concentration of compound which inhibitsmuscarinic 3 receptor response 50% of its maximum response) below 10 μMprovide such inhibition. Further, based on testing with at least oneother muscarinic 3 receptor antagonist with IC₅₀ value at level of 10μM, applicants have noted that this concentration provides significantlyenhanced cell proliferation. As seen, all the novel compounds of theinvention have IC₅₀ value well below 10 μM.

TABLE 1 Structure IC₅₀ Example ID Structure (μM)  1 3a

5.3  2 3b

2.1  3 3c

1.4  4 3d

7.9  5 3e

0.0095  6 3f

0.409  7 3g

0.060  8 7a

1.8  9 7b

2.1 10 7c

0.599 11 7d

0.063 12 7e

0.195 13 7f

4.7 14 7g

0.144 15 7h

3.0 16 7i

4.6 17 7j

0.266 18 9a

6 19 9b

0.609 20 9c

1.2 21 9d

0.357 22 9e

5.7 23 9f

0.346 24 9g

3.9 25 9h

2.7 26 11

4.3 27 13

1.4

The results below show a representative N-aralkylcarbonyl-piperazine(7d) (Example 29) and a N-aralkylcarbonyl-homopiperazine (3e) (Example28) included in this invention effectively increasing cell proliferationin human living skin equivalents as measured by Ki-67 staining (Table2).

TABLE 2 % Increase in Ki-67 stained positive cells Structure Concen-over Example ID Structure tration vehicle P-value 28 3e

10 μM  56 0.0009 29 7d

10 μM 127 0.003 

Specifically, these compounds provide an increase in Ki-67-stainedpositive cells (more proliferation) of 56% and 127%, respectively.

The controlled effect and relative position of the amide bond and thetertiary amine group for the compounds included in this invention arecritical elements to achieve lower basicity (measured by drop in pH ofsolution of 0.3-4.0 pH units) while maintaining high efficacy. Forexample, representative N-aralkylcarbonyl-piperazine (3c) (Example 30)(Table 3) included in this invention is less basic than itscorresponding secondary amine derivative (6b) (Example 31) (outside ofthis invention), as demonstrated by direct comparison of the measuredpH's from equimolar solutions of each compound (Table 3). In going fromsecondary amine (6b) with a pH of 10.0 to the corresponding tertiaryamine (3c) with a pH of 8.5 there is a 1.5-unit reduction in pH,demonstrating the higher basicity of secondary amine compound (6b).Further evidence demonstrating the inductive effect of the amide bond onthe tertiary amine group of the piperazine core structure containedwithin the compounds of this invention is illustrated by directcomparison of the pH measured between compound (14) (Example 32)(outside of this invention) with a pH of 11.0 and (3c) (Example 30) witha pH of 8.5 which resulted in a 2.5 unit pH reduction in favour of theamido compound (3c). Similarly, representativeN-aralkylcarbonyl-homopiperazine (3e) (Example 33) included in thisinvention is less basic compared to its corresponding secondary aminederivative (6j) (Example 34) (outside of this invention) as demonstratedby a pH reduction of 0.9 units in favour of (3e). Taking into accountthe inductive effect of the amido group of the inventive homopiperazine(3e), a total pH reduction of 2.45 units was observed relative to itsnon-amido homopiperazine compound (15) (Example 35). Overall, thecombination and relative position of these critical elements (amide bondand tertiary amine functionality) render the compounds of this inventionless basic and more suitable for topical skin application whileeffective at inhibiting the muscarinic 3 receptor and increasing cellproliferation compared to compounds lacking these critical elements.

TABLE 3 Measured Structure pH of Example ID Structure solution 30 3c

8.5 31 (Com- para- tive) 6b

10.0 32 (Com- para- tive) 14

11.0 33 3e

9.0 34 (Com- para- tive) 6j

9.9 35 (Com- para- tive) 15

11.5

Example 36

Herein is illustrated a lotion according to the present invention with aformula as outlined in Table 30 below. This formula is packaged in astandard polypropylene bottle with screw-top. A label around the outsideof the bottle specifies that the composition has effectiveness againstthe signs of aging including removal of fine lines and wrinkles.

TABLE 4 INGREDIENT WEIGHT % PHASE A Water Balance Disodium EDTA 0.05Methyl Paraben 0.15 Magnesium Aluminum Silicate 0.60 Triethanolamine1.20 Compound 3e 0.1 PHASE B Xanthan Gum 0.20 Natrosol ® 250HHR (ethylcellulose) 0.50 Butylene Glycol 3.00 Glycerin 2.00 PHASE C SodiumStearoyl Lactylate 0.10 Glycerol Monostearate 1.50 Stearyl Alcohol 1.50Isostearyl Palmitate 3.00 Silicone Fluid 1.00 Cholesterol 0.25 SorbitanStearate 1.00 Butylated Hydroxy Toluene 0.05 Vitamin E Acetate 0.01PEG-100 Stearate 2.00 Stearic Acid 3.00 Propyl Paraben 0.10 Parsol MCX ®2.00 Caprylic/Capric Triglyceride 0.50 Hydroxycaprylic Acid 0.01 C12-15Alkyl Octanoate 3.00 PHASE D Vitamin A Palmitate 0.10 Bisabolol 0.01Vitamin A Acetate 0.01 Fragrance 0.03 Retinol 50C 0.02 ConjugatedLinoleic Acid 0.50

Example 37

A water-in-oil topical liquid make-up foundation according to inventionis described in Table 5 below. This foundation is delivered via a glassscrew-top capped bottle. The bottle is placed within an outer carton.Inside the carton is placed instructions for use including applying thefoundation to the face to achieve improvements in the signs of agingincluding enhanced radiance.

TABLE 5 INGREDIENT WEIGHT % PHASE A Cyclomethicone 9.25 Oleyl Oleate2.00 Dimethicone Copolyol 20.00 PHASE B Talc 3.38 Pigment (Iron Oxides)10.51 Spheron L-1500 (Silica) 0.50 PHASE C Synthetic Wax Durachem 06020.10 Arachidyl Behenate 0.30 PHASE D Cyclomethicone 1.00Trihydroxystearin 0.30 PHASE E Laureth-7 0.50 Propyl Paraben 0.25 PHASEF Fragrance 0.05 PHASE G Water balance Compound 3e 0.1-1.0 MethylParaben 0.12 Propylene Glycol 8.00 Niacinamide 4.00 Glycerin 3.00 SodiumChloride 2.00 Sodium Dehydroacetate 0.30

Example 38

Illustrated herein is a skin cream incorporatingN-aralkylcarbonyl-piperazine compound(s) of our invention. The cream isdeposited in a wide-mouth jar with screw-cap top. Printed on the labelof the jar are instructions that the cream will control the signs ofaging such as hyperpigmentation and sagging skin.

TABLE 6 INGREDIENT WEIGHT % Glycerin 6.93 Niacinamide 5.00 Compound 3e0.1 Permethyl 101A¹ 3.00 Sepigel 305² 2.50 Q2-1403³ 2.00 Linseed Oil1.33 Arlatone 2121⁴ 1.00 Cetyl Alcohol CO-1695 0.72 SEFA Cottonate⁵ 0.67Tocopherol Acetate 0.50 Panthenol 0.50 Stearyl Alcohol 0.48 TitaniumDioxide 0.40 Disodium EDTA 0.10 Glydant Plus⁶ 0.10 PEG-100 Stearate 0.10Stearic Acid 0.10 Purified Water Balance ¹Isohexadecane, Presperse Inc.,South Plainfield, NJ ²Polyacrylamide(and)C13-14 Isoparaffin(and)Laureth-7, Seppic Corporation, Fairfield, NJ³dimethicone(and)dimethiconol, Dow Corning Corp. Midland, MI ⁴SorbitanMonostearate and Sucrococoate, ICI Americas Inc., Wilmington, DE⁵Sucrose ester of fatty acid ⁶DMDM Hydantoin (and) IodopropynylButylcarbamate, Lonza Inc., Fairlawn, NJ

Example 39

Illustrative of another cosmetic personal care composition incorporatingN-aralkylcarbonyl-piperazine compounds of our invention is the formulaof Table 7. This composition is packaged in a plastic polypropylene tubewith flexible side walls for pressing the composition through a tubeorifice. Instructions are printed on the outside of the tube directingthat the composition be applied to the face and that in a period fromabout 2 weeks to about 6 months, the signs of aging will havediminished.

TABLE 7 INGREDIENT WEIGHT % Polysilicone-11 29 Cyclomethicone 59Petrolatum 11 Compund 3e 0.2 Dimethicone Copolyol 0.5 Sunflowerseed Oil0.3

Example 40

A skin conditioning lotion is prepared as follows:

Ingredient % by Weight Water Balance Carbopol Ultrez 10 0.8Polyoxyethylene 21 stearyl ether 0.4 Polysorbate 60 0.3 Glycerine 10.0Preservative 0.7 Dimethicone crosspolymer 10 NaOH (50%) 0.5 Dimethicone11.0 Compound 3e 0.5 Mineral oil 2.0 Polyethylene 4 Fragrance 0.3

1. An N-aralkylcarbonylpiperazine or N-aralkylcarbonylhomopiperazinecompound having structure I noted below:

wherein n=0 or 1, and wherein, when n=1, R₁ is selected from hydrogen orhydroxyl, R₂ is selected from cyclohexyl or cyclopentyl and R₃ isselected from the group consisting of C₁-C₃ alkyl or C₁ to C₄ arylalkyl,wherein a C₁ to C₄ alkyl group is directly attached to the aryl group;and when n=0, R₁ is selected from hydrogen or hydroxyl, R₂ is selectedfrom cyclohexyl or cyclopentyl and R₃ is selected from the groupconsisting of C₁-C₈ alkyl, wherein the C₁ to C₈ group is linear, cyclicor branched; arylalkyl where the alkyl component has C₁ to C₄ chain,wherein the alkyl group is linear, branched, saturated, or unsaturated,and the alkyl group is unsubstituted or substituted with one or two C₁to C₃ alkyl or alkoxy groups; aroylalkyl, wherein the alkyl group isunsubstituted or substituted with one or two C₁ to C₃ alkyl oralkoxygroups; arylalkanoyl; or aryloxyalkyl; wherein compounds wheren=0, R₁=hydrogen, R₂=cyclohexyl and R₃=benzyl or(E)-3-phenylprop-2-en-1-yl are specifically excluded; and amine saltsthereof;
 2. A compound according to claim 1, wherein n=1, R₁ ishydroxyl, R₂ is cyclopentyl and R₃ is C₁ to C₃ alkyl.
 3. A compoundaccording to claim 1, wherein n=1, R₁ is hydroxyl, R₂ is cyclopentyl andR₃ is methyl.
 4. A compound according to claim 1, wherein n=1, R₁ ishydroxyl, R₂ is cyclohexyl and R₃ is methyl.
 5. A compound according toclaim 1, wherein n=1, R₁ is hydrogen, R₂ is cyclopentyl and R₃ ismethyl.
 6. A compound according to claim 1 wherein n=0, R₁ is hydroxyl,R₂ is cyclopentyl and R₃ is an aryl-C₃-alkyl group.
 7. A compoundaccording to claim 1, wherein the compound is not quaternized.
 8. Acompound according to claim 1, wherein pKa of compound of Structure I islower than
 9. 9. A compound according to claim 1 provides a drop invalue of pH, when comparing pH in solution of invention compoundsrelative to comparative compound which is identical except it hassecondary amine versus tertiary amine, of 0.3-4 pH units, wherein the pHof solution is measured by dissolving equimolar amounts of inventive orcomparative compound in organic solvent and diluting with sufficientwater to provide a 1 to 5% solution, preferably 2 to 4% solution(weight/volume) of the compounds in a water-organic solvent homogeneoussolution.
 10. A personal care composition comprising: a) about 0.001 to20% by wt. of composition of a compound or compounds selected from thegroup consisting of (i) N-aralkylcarbonyl-piperazine compound orcompounds, (ii) N-aralkylcarbonylhomopiperazine compound or compounds,and (iii) mixtures of (i) and (ii) where said N-aralkylcarbonylpiperazine or N-aralkylcarbonylhomopiperazine compound has Structure Inoted below:

wherein n=0 or 1, and wherein when n=1, R₁ is selected from hydrogen orhydroxyl, R₂ is selected from cyclohexyl or cyclopentyl and R₃ isselected from the group consisting of C₁-C₃ alkyl or C₁ to C₄ arylalkyl;and when n=0, R₁ is selected from hydrogen or hydroxyl, R₂ is selectedfrom cyclohexyl or cyclopentyl and R₃ is selected from the groupconsisting of C₁-C₈ alkyl, wherein the C₁ to C₃ group is linear, cyclicor branched; arylalkyl, wherein the alkyl group is linear, branched,saturated, or unsaturated, and the alkyl group is unsubstituted orsubstituted with one or two C₁ to C₃ alkyl or alkoxygroups; aroylalkyl,wherein the alkyl group is unsubstituted or substituted with one or twoC₁ to C₃ alkyl or alkoxy groups; arylalkanoyl; or aryloxyalkyl; whereincompounds where n=0, R₁=hydrogen, R₂=cyclohexyl and R₃=benzyl or(E)-3-phenylprop-2-en-1-yl are specifically excluded; and amine saltsthereof b) a cosmetically acceptable vehicle which may range from 5 to99% by wt. of the composition; and c) optional skin benefit materialand/or cosmetic adjunct.
 11. A composition according to claim 10 whereinthe compound of Structure I is non-quaternized.
 12. A compositionaccording to claim 10 wherein pKa of the compound of Structure I is lessthan
 9. 13. Use of any of the compounds of claim 1 enhancing cellproliferation.
 14. Use of any of the compounds of to enhance cellmigration.
 15. Use of any of the compounds of claim 1 to increaseepidermal thickness.